Abstract

Neurodevelopmental disorders (NDDs), including intellectual disability (ID) and autism spectrum disorders, are phenotypically and genotypically heterogeneous. One increasing group of NDDs is caused by mutations in epigenetic regulators of gene expression. Recent studies have identified Euchromatin Histone Methyltransferase 1 (EHMT1) as a key modulator in cognition. Heterozygous loss of EHMT1 causes Kleefstra syndrome, which is characterized by moderate-to-severe ID, autistic behaviour, microcephaly and dysmorphic features. While the identification of disease genes has great benefits for diagnostic and prognostic purposes, for the vast majority of these genes there is little knowledge about neurobiological mechanisms that they control at the cellular and network level.

Here, we studied the effect of EHMT1-deficiency on neuronal activity in-vitro using neurons derived from Induced Pluripotent Stem Cells (iPSC). Using micro-electrode arrays (MEAs) technology and whole-cell patch-clamp recordings we characterized the electrophysiological activity of neuronal cultures derived from healthy subjects and Kleefstra patients on both network- and single-cell level in vitro. We show that neurons derived from Kleefstra patients iPSCs on MEAs exhibited different pattern of synchronous activity compared to control condition. In particular, we showed that EHMT1-deficiency induces an inappropriate network organization and irregular pattern of activity, indicating that EHMT1 is required for proper network organization.